IO/TKI Combinations Shift the Standard of Care in Renal Cell Carcinoma

First-line treatment with VEGF receptor tyrosine kinase inhibitors (TKIs) has demonstrated benefit in advanced renal cell carcinoma (RCC), but most patients eventually experience disease relapse as resistance develops over time. Sunitinib (Sutent), a multitargeted TKI, was the established standard of care against which new regimens were benchmarked.

Three trials, CheckMate 9ER (NCT03141177),¹ KEYNOTE-426 (NCT02853331),² and the CLEAR study (NCT02811861),³ were designed based on the same overarching biological principle: that RCC is uniquely susceptible to both antiangiogenic and immunotherapeutic approaches, and that combining the 2 modalities might be synergistic.

In a live event, Thomas Hutson, DO, PharmD, PhD, and participants discussed these trials and explored evolving strategies in RCC.

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CASE SUMMARY

• A 65-year-old man presented with back pain for past 6 months and hematuria for 1 week.
• Laboratory findings
  • Hemoglobin: 11.4 g/dL
  • Lactate dehydrogenase: 980 U/L
  • All others within normal limits
• CT of chest, abdomen, and pelvis showed high disease burden, including multiple mediastinal and hilar nodes, deposits in left lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium.
• Biopsy of renal mass and bone biopsy confirmed metastatic clear cell renal cell carcinoma.
• The patient received cabozantinib (Cabometyx) plus nivolumab (Opdivo).

DISCUSSION QUESTIONS

After reviewing the CheckMate 9ER, KEYNOTE-426, and CLEAR trials, what is your preferred regimen?

• Why? If your preference has changed, what impacted your decision?
  • Patient characteristics
  • Disease characteristics
  • Efficacy data
  • Safety data
  • Other

Thomas Hutson, DO: The CLEAR trial was a 3-arm trial, and the statistical design compared each of the 2 lenvatinib (Lenvima)-containing arms independently to sunitinib. Importantly, the trial was not designed to compare the 2 lenvatinib arms to each other.

The lenvatinib plus everolimus arm tends to be overlooked in discussions of this trial, but it did demonstrate superiority over sunitinib. This is analogous to CheckMate 9ER, where cabozantinib-based therapy outperformed sunitinib. Similarly, the lenvatinib plus everolimus arm beat sunitinib—but this finding generated little excitement, because the clinically compelling result was in the lenvatinib plus pembrolizumab (Keytruda) arm.

The primary end point of the CLEAR trial was progression-free survival [PFS], with overall survival as a key secondary end point. Most people chose this regimen over the other 2.

Does anyone have anything to add?

Manmeet Mangat, MD: There’s no one particular regimen that is better, as we know. There’s no accurate comparison, but with the response rates, I think the [lenvatinib plus] pembrolizumab regimen seems to be the one that is most efficacious, and where there’s need for urgent response, that’s something that we would suggest.

Donald Richards, MD: What you’re most familiar with is probably going to be your best choice.

Hutson: Let’s move on to dual immune checkpoint inhibitors (ICIs) for metastatic RCC. That brings us to CheckMate-214 (NCT02231749).⁴ This represents the IO/IO data in first-line advanced RCC. The trial’s primary end points were objective response rate (ORR), overall survival (OS), and PFS, assessed in the intermediate- and poor-risk population specifically.

One notable aspect of this trial’s design is the handling of the favorable-risk subgroup. While favorable-risk patients were enrolled, this subgroup was not part of the primary analysis and received little attention early on. The OS advantage in the favorable-risk group only emerged as a late finding, at which point it gained more prominence — but by then, the field had largely moved on. This selective reporting of the favorable-risk data at the time of initial presentation is worth keeping in mind when interpreting the trial’s full scope.

DISCUSSION QUESTIONS

What other factors drive your selection of first-line therapy for metastatic ccRCC? For example:

• Efficacy
• Overall response/complete response
• Is PD important to you in terms of clinical decision making?
• Progression-free survival
• Overall survival, as data mature
• Quality of life/safety
• Performance status
• Symptom burden
• Tumor burden
• Risk status
• Patient preference
• Other

Hutson: what other factors drive your selection of first line therapy for metastatic RCC?

Miguel Albino, MD: Beyond what has already been discussed — symptomatic disease and high burden — comorbidities weigh heavily in my decision-making. Patients with hypertension, for example, can be particularly challenging to manage on TKI-based regimens. The toxicity profile of TKIs, including the risk of stroke and other cardiovascular complications, can make dosing difficult and significantly affect tolerability.

So for me, in addition to the factors already covered, the key considerations are: the patient’s comorbidity profile, patient preference, and the aggressiveness of the disease course. RCC is a heterogeneous disease — many patients follow an indolent trajectory, but some do not — and that biological behavior factors into my thinking as well.

In short, outside of the more straightforward clinical indicators, much of my decision-making comes down to comorbidities.

Ananth Arjunan, MD: One additional factor worth highlighting is the complete response rate achieved with the CLEAR regimen. While cross-trial comparisons are difficult, CLEAR demonstrated a CR rate of approximately 18%, and importantly, that rate appears to plateau and be sustained at 3 years—suggesting these are durable complete responses.³ By comparison, other regimens have shown CR rates in the range of approximately 12%.^1,2 Does that difference in CR rate factor into your decision-making? For me, the higher CR rate is a favorable attribute of the CLEAR regimen and is something I weigh when choosing between first-line options.

Hutson: For me, the CLEAR regimen is my preferred choice largely because I feel it offers the greatest probability of achieving meaningful tumor shrinkage and deep responses. But that said, you raise a fair point—it is genuinely difficult to parse meaningful differences between these regimens. At the end of the day, it is probably better to become comfortable with one regimen and use it consistently rather than trying to over-interpret cross-trial comparisons.

I would also add that the landscape may be shifting. We may be entering a new era in the treatment of advanced RCC in the not-too-distant future, with emerging data and approaches that could change how we think about first-line therapy — so stay tuned.

Mangat: Isn’t it also true that there are some who don’t respond at all to IO/IO?

Huston: Yes, approximately 1 in 5 patients achieve a complete response.⁴

Mangat: The challenge is to determine which of the 18% you will fall under.

Rashad Khan, MD: Aren’t the patients who have sarcomatoid disease the patients who might benefit from dual IO?

Hutson: Yes, patients with sarcomatoid RCC do appear to benefit from IO-based therapy. Now, to definitively answer whether they derive greater benefit from an IO/IO regimen versus lenvatinib plus pembrolizumab would require a dedicated randomized trial—we don’t have that direct comparison. But the biological rationale is clear: sarcomatoid histology is associated with greater tumor mutational burden, and these tumors respond better to checkpoint inhibition in general.³

It is worth putting this in historical context. When we were running the first-generation trials with agents like sorafenib (Nexavar) and sunitinib, patients with sarcomatoid [RCC] were actually excluded from enrollment—there was a concern that they were poor-prognosis patients who were unlikely to respond. With the advent of checkpoint inhibitors, that thinking reversed entirely. These patients were actively encouraged to enroll because we recognized they were more likely to respond. And that has borne out across trials.

DISCLOSURES: Hutson reported receiving research support from Bayer/Onyx, Pfizer, and GlaxoSmithKline, and he is an advisory board/consultant for Bayer/Onyx and Pfizer and on the speaker's bureau for Bayer/Onyx, Pfizer, Amgen, Novartis, and Genentech.

REFERENCES

1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nat Med. 2025;31(10):3475-3484. doi:10.1038/s41591-025-03867-5

3. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569

4. Tannir NM, Albigès L, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2024;35(11):1026-1038. doi:10.1016/j.annonc.2024.07.727